Ras family GTPases are critical components of cell regulatory systems that control proliferation, differentiation, and cell survival. Inappropriate regulation of these systems directly contributes to initiation and progression of human cancer. This proposal is directed at decoding the composition, organization, and function of cell regulatory networks engaged by Ras family GTPases. Our focus is on isolation of molecular fulcrums that can be exploited to deflect oncogenic Ras-induced corruption of cell proliferation and survival restraints. Our specific aims are 1) mechanistic elaboration of TBK1 as an oncology target in oncogenic Ras associated cancers;2) capture of oncogenic Ras synthetic-lethal loci by matrix analysis of pangenomic RNAi screens;and 3) comprehensive mapping of the human kinome to EGF receptor signaling. PUBLIC HEALTH RELEVANCE: Progress in annotation of the signaling repertoire of oncogenic Ras in human cancer presents an exciting opportunity to identify effective interventions for tumors harboring this mutation. The key bottleneck to progress has been the struggle to identify effective targetable pressure-points within the oncogenic Ras regulatory network. We are applying leading-edge strategies to decode the linchpin elements mediating oncogenic Ras transformation. The expected outcomes and impact of our proposal will be isolation of molecular fulcrums, selectively supporting oncogenic Ras-induced perturbation of regulatory networks, that can be exploited to undercut tumor cell proliferation and survival. We have extensive experience and institutional support to carry out this project.